Novel 7{60 -methyl-13{62 -alkyl-18,19-dinor/{66 {11 {11 {11 {11 {11 pregnatrienes

ABSTRACT

Novel 7 Alpha -methyl-13 Beta -alkyl-18,19-dinor- Delta 4,9,11pregnatrienes of the formula   WHEREIN R is alkyl of one to three carbon atoms and R&#39;&#39; is selected from the group consisting of hydrogen, alkyl of one to three carbon atoms and OR&#39;&#39;&#39;&#39; wherein R&#39;&#39;&#39;&#39; is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms having very intense antiandrogenic activity without manifesting antihypophysical properties with LH predominance to weak degree and to novel process and intermediates.

United States Patent 1 Bucourt et al.

[ June 18, 1974 NOVEL 7a-METHYL-l3B-ALKYL-18J9-DINOR- A PREGNATRIE NE S Inventors: Robert Bucourt; Andr Pirdet,

both of Noisy-le-Sec, France Assignee: Roussel Uclaf, Paris, France Filed: Nov. 28, 1972 Appl, No.: 310,169

Foreign Application Priority Data Dec. 8, 1971 France 71.44013 US. Cl 260/397.3, 260/397.45, 424/242 Int. Cl. C07C 169/34 Field of Search lMachine Searched Steroids References Cited UNITED STATES PATENTS 4/1967 Bucourt et a1. 167/74 10/1967 Bucourt et a1. 167/74 1/1969 Joly et a1. 260/2395 7/1969 Vignau et al 260/239.55

Primary ExaminerHenry A. French Attorney, Agent, or Firm-Hammond & Littell 5 7] ABSTRACT Novel 7a-methy1- l 3B-alky1- l 8, l 9-dinor-A pregnatrienes of the formula 3 Claims, No Drawings 1 NOVEL 7a-METHYL-13B-ALKYL-l8,l9- DINORA 1 -PREGNATRIENES STATE OF THE ART U.S. Pat. No. 3,346,454 describes l9-nor-A-"'- pregnatrienes of the formula wherein R and R are alkyl of one to four carbon atoms having progestative and progestomimetic activities.

OBJECTS OF THE INVENTION THE INVENTION The 7a-methyll 3B-alkyli 8, l 9-dinor-A' "-pregnatriene-3,20-diones of the invention have the formula wherein R is alkyl of one to three carbon atoms and R is selected from the group consisting of hydrogen, alkyl of one to three carbon atoms and OR" wherein R" is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms. Preferably, R is methyl and R is hydrogen and where R is acyl, it is preferably derived from a hydrocarbon carboxylic acid.

Examples of suitable acids are alkanoic acids, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid trimethyl acetic acid, caproic acid, B-trimethylpropionic acid, heptanoic acid, caprylic acid, pelarginic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoic acids such as cyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids such as phenylacetic acid and phenylpropionic acid; aryl carboxylic acids such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxyacetic acid, p-chlorophenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4-tert.- butylphenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids such as furane-Z-carboxylic acid, 5-tert.- butylfurane-Z-carboxylic acid, 5-bromofurane-2 carboxylic acid and nicotinic acids; B-ketoalkanoic acids such as acetylacetic acid, propionylacetic acid and butyrylacetic acid; amino acids such as diethylaminoacetic acid and aspartic acid.

The novel process of the invention for the preparation of the compounds of formula I comprises subjecting a ketal of the formula O CH:

R ll

l O "CH:

III

reacting the latter with a hydroperoxidation agent to for m a compound of the formula reducing the latter with a reducing agent to form a swwnq 9 the. formula and dehydrating the latter with a mineral acid to form the corresponding compound of formula I.

The hydrolysis of the compound of formula II may be effected with an organic carboxylic acid such as formic acid, acetic acid, citric acid or tartaric acid in an aqueous media or in the presence of a polar solvent such as an alkanol like methanol or ethanol or in the presence of a nonpolar solvent such as chloroform, dioxane, tetrahydrofuran or benzene. Hydrolysis may also be effected by functional exchange with an a-aldehydic acid or a-ketonic acid such as glyoxalic acid, pyruvic acid or tartronic acid. Also usable is an aldehyde or ketone in the presence of a mineral or organic acid such as formol in the presence of hydrochloric acid.

The hydroperoxidation of the compound of formula Ill may be effected by bubbling oxygen or air therethrough in the presence of a tertiary amine such as triethylamine or pyridine. The reducing agent may be an alkyl phosphite, or alkyl sulfide or an alkali metal iodide such as potassium iodide in the presence of an alkanoic acid such as acetic acid. The dehydration of the compound of formula V is effected with a strong mineral acid such as perchloric acid or sulfuric acid in the presence of a polar solvent such as acetonitrile or trifluoroacetamide.

The starting compounds of formula II wherein R is hydrogen and R, R, and R have the above definitions may be prepared by reacting a compound of the formula a with a triarylethylphosphonium halide in a basic media to obtaina compound of the formula oxide to obtain a compound of the formula R OH i H-CHa VIII a t, A v H IX which may be esterified with an organic carboxylic acid or a functional derivative thereof or if desired may be reacted with a dehydrated agent to form a compound of the formula reducing the latter with an alkali metal and reacting the resulting carbanion with an alkyl halide in the presence of an alkali metal to obtain the compound of formula ll wherein R is alkyl of one to three carbon atoms.

The compounds of formula H], W and V are novel products.

The novel antiandrogenic compositions of the invention are comprised of an effective amount of a compound of formula l and a pharmaceutical carrier. The compositions may be in the form of in jectable solutions or suspensions in ampoules or multiple dose flacons or in the form of tablets, coated tablets, emulsions, gelules, or suppositories prepared in the usual fashion.

The compositions possess very intense exogenic antiandrogenic activity so that they are useful in human theraphy against pathological manifestations of juvenile acne such as comedos, papulo-pustuls. tuberculopustuls or deep nodules. facial seborrhea and hairy skin and against adenoma of the prostate. The compounds of formula I are differentiated from known l9-norpregnatriene-3,20-diones by very sensibly diminished central properties as they do not manifest antihypophysial properties with LH predominance to a weak degree and equally manifests antiestrogenic activity even at elevated dosages.

The novel method of the invention for the treatment of hyperandrogenia comprises administering to warmblooded animals an antiandrogenic amount of a compound of formula I. The compounds may be adminis' tered rectally, orally or parentally. The usual daily use- EXAMPLE Preparation of 7a-methyl-19-nor-A' -"-pregnatriene- 3,20-dione Step A:

3,3-dimethoxy-7a-methyl-19-norpregnatriene A solution of 2.04 g of potassium tert.-butylate and 6.75 g of triphenylethylphosphonium bromide in 30 ml of tetrahydrofuran was refluxed for minutes and after cooling the solution to C, 2 g of 3,3-

dimethoxy-7a-methyl-A -estradiene-l7-one (described in British Pat. No. 1,127,747) were added thereto. The mixture was stirred at room temperature for 15 hours and was then poured into a water-ice mixture. The tetrahydrofuran was distilled off at 40C under reduced pressure and the aqueous phase was ex tracted with benzene. The benzene extracts were washed with water, dried over sodium sulfate and evaporated to dryness to obtain 7.4 g of a mixture of 3,3- dimethoxy-7a-methyl-19-nor-A"-"""" pregnatriene and 3-methoxy-7a-methyl- 1 9-nor- A"' -pregnatetraene which was used as is for the next step.

To obtain the pure 3,3-dimethoxy compound, the residue was chromatographed over silica and was elut ed with a 9 1 mixture of benzene and ethyl acetate. After crystallization from isopropyl ether, the product occurred in the form of colorless crystals soluble in ethanol, benzene, ether and acetone and insoluble in water. The product melted at 94C and had a specific rotation [6111, 154 (C 1 percent in ethanol containing 1 percent pyridine).

50 ml of distilled water were added to a solution of 12.76 g of the mixture of Step A in 150 ml of acetic acid and the mixture was stirred for 1 hours at room temperature. The mixture was poured into an ice-water mixture which was then vacuum filtered. The precipitate was washed with water until the wash waters were neutral and then dried under reduced pressure to obtain 1 1.12 g of 7a-methyl-19-nor-A pregnatriene-B-one which was used as is for the next stage. The product occurred in the form of colorless crystals melting at 80C and soluble in alcohols and benzene and insoluble in water.

LEV. Spectrum 1 ethanol 1:

Max. at 241 nm 6 18.950

1 1.12 g of 7a-methyl-l9-nor- -pregnatriene-3-one, 550 ml of benzene, 550 ml of methylethyldioxolane and 1 1 ml of ethyleneglycol was refluxed with stirring and after the addition of 334 mg of p toluene-sulfonic acid thereto, the mixture was refluxed for 3 Z1 hours. After cooling to 20C, 50 ml of an aqueous saturated sodium bicarbonate solution were added thereto and the mixture was stirred under a nitrogen atmosphere for 30 minutes. The aqueous phase was decanted and extracted with benzene. The organic phase was washed with water, then with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 8.163 g of 3,3-ethylene-dioxy-7a-methyl-l9-nor- A -pregnatriene melting at 124C. Evaporation of the mother liquor to dryness and chromatography of the residue gave a second yield of 7 percent of the product for a total yield of 74.5 percent melting at 124C. The pure product occurred in the form of colorless crystals melting at 124C and had a specific rotation [01],, 151(C= 1% in ethanol containing 1 percent of benzene). The product wassoluble in ethanol, benzene and'chloroform and insoluble in water.

A mixture of A5( l0),9(11),17(20) Calculated: "/(C 111.13 '/:H 9.47 Found: 81.1 9.3

STEP D:

3,3-ethylenedioxy-7a-methyl-19-nor- A """-pregnadiene-20a-ol 16.27 g of 3,3-ethylenedioxy-7a-methyl-l9-nor- A""""""" -pregnatriene were dissolved in ml of tetrahydrofuran by stirring under a nitrogen atmosphere, and after cooling the solution to 0 to 5C, 129 ml ofa solution of diborane in tetrahydrofuran titrating 1.51 g of per 100 ml in boron hydride. The mixture was stirred under nitrogen for minutes at 0C after cooling to 5C, 24 ml of water and then a solution of 24 ml of water, 24 ml of sodium hydroxide and 71 ml of ethanol were added thereto. Then, 48 m1 of a 1 10 volumes hydrogen peroxide solution were added thereto and the mixture was stirred for 1 hour at 0C. The mixture was poured into a water-ice mixture which was then extracted with methylene chloride. The organic phase was washed with water until the wash water was neutral, dried over sodium sulfate and then evaporated to dryness. The residue was chromatographed over silica and was eluted with a 5-5 benzene-ethyl acetate mixture. Evaporation of the eluant gave 14.967 g of 3,- 3-ethy1enedioxy-7a-methyll 9-nor-A "-pregnadiene-20a-ol which was-used as is for the next step.

LR. Spectrum tchloroforml Presence of kctal. of C=C and of 2001-01 U.\'. Spectrum {ethanol} Step E: 3,3-ethylenedioxy-7a-metyl-19-nor-A pregnadiene-ZO-one A mixture of 13 g of 3,3-ethylenedioxy-7a-methyll9-nor-A ""-pregnadiene-20a-ol, 1 13 ml of cyclohexanone and 1,930 mi of toluene was refluxed under a nitrogen atmosphere while distilling off 200 ml of solvent and then a solution of 17.4 g of aluminum isopropylate in a liter of toluene was added thereto while distilling off a liter of solvent. The mixture was cooled to room temperature and a solution of 65 g of potassium carbonate, 130 g of sodium potassium tartrate and L300 ml of water was added thereto with stirring under an inert atmosphere. The solvents were entrained with water and after cooling, the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 7-3 benzene-ethyl acetate mixture. Evaporation of the eluant gave 9.035 g of 3,3-ethylenedioxy-70z-methyl-l9-nor- A """-pregnadiene --one melting at 1l4C. The product occurred as a colorless solid soluble in alcohols, benzene and acetone and insoluble in water. LR. Spectrum (chloroform): Presence of non-conjugated ketone at l,696"" and of ketal. Step F: 7a-methyl-i9-nor-A ""-pregnadiene-3,20- dione A solution of 9.2 g of 3,3-ethylenedioxy-7a-methyll9-nor-A "-pregnadiene-ZO-one in 92 ml of 75 percent acetic acid was stirred under a nitrogen atmosphere and was then heated at 55C for 3 /2 hours. After cooling, the mixture was added to water and the mixture was neutralized with sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness to obtain 8.179 g of 'la-methyll 9-nor-A -pregnadiene-3,20-dione which was used as is for the next step. The product occurred as a pale yellow solid melting at lO8C and was soluble in alcohols and benzene and insoluble in water.

LIV. Spectrum (ethanol Step G: 7a methyl-l lB-hydroperoxy-l9-nor-A"-pregnadiene-3.20-dione Oxygen was bubbled at room temperature through a solution of 8. 16 g of 7a-methyl-l9-nor-Ahu 5( l0).9( ll)-pregnadiene-3.20-dione in 82 ml of ethanol containing 1 percent triethylamine for 20 hours and the mixture was vacuum filtered. The precipitate was washed with iced ethanol and dried under reduced pressure to obtain 4.838 g of 7a-methyl-l lB-hydroperoxyl9 nor- A -pregnadiene-3.ZO-dione melting at 250C. Evaporation of the mother liquors to dryness gave a second crop of 4.6 g of product for a total yield of 76 percent. The product occured as a pale yellow solid soluble in ethanol and benzene. slightly soluble in ether and insoluble in water. LR. Spectrum (chloroform): Presence of non-conjugated ketone at l,702"". of conjugated ketone at l,66l""", of C=C at L608 and of OH at 3520".

UN. Spectrum (ethanol):

Step H: 7a-methyl-l9nor-A-"-pregnadiene-l lB-ol- 3,20-dione 2.4 ml of trimethyl phosphite were added under an inert atmosphere to a suspension of 4.825 g of 7amethyl-1 lB-hydroperoxy-19-nor-A' -pregnadiene- 3,20-dione in 24 ml of methanol and the mixture was stirred for 40 minutes at room temperature. The ml mixture was added to a solution of 240m of water and 12ml of a 1 10 volumes hydrogen peroxide solution and was stirred for 15 minutes. The mixture was then extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate and evaporated to dryness to obtain 4.53 g of 7a-methyll9-nor-A -pregnadiene-l lB-ol-3,20-dione melting at 248C. The product occurred as a colorless solid soluble in ethanol and benzene, slightly soluble in ether and insoluble in water. LR. Spectrum (chloroform): Presence of non-conjugated ketone at l,702""' with a oz-methyl at l.355""'. of complex dienone at 1661 of C=C at 1,608 and l,585" and of OH UV. Spectrum g ethanol Max. at 217 nm E,,.,,,"" 14*;

Maxv at 299L399 nm E 594 e I LSUU Step I: 7oz-methyl-lQ-nOrA '-pregnatriene-3.2(l-

dione A mixture of 5.16 g of 7a-methyl-l9-nor-A pregnadiene-l l,B-ol-3,20-dione, 900 ml of methylene chloride. 22 ml of acetonitrile and 8.4 ml of perchloric acid was stirred at room temperature for 2 k minutes and was then poured in an aqueous sodium bicarbonate solution. The organic phase was decanted and the aqueous phase was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 3.494 g of 7a-methyl-l9 nor- A -pregnatriene-Z,ZO-dione melting at 133C and having a specific rotation [01],, +l 7.5( c 0.5 percent in ethanol)v The product occurred as pale yellow crystals soluble in alcohols and benzene and insoluble in water.

8.44 Found: 8 l .3 8.4

PHARMACOLQGICAL DATA A. Antigonadotrophic Activity The antigonadotrophic activity of 7arnethyl-l9-nor- A -pregnatriene-3.2O-dione was determined on puberic rats weighing about 200 g by subcutaneous administration in a volume of 0.2 ml in solution in sesame oil containing 5 percent benzyl alcohol. There were l2 treatments over 14 days at a daily dose of 2 mg per animal. On the 15th day. the animals were killed by carotidienne bleeding and the seminal vesiculs prostate, testicules and surrenals were recovered and weighed. The results are reported in Table l.

TABLE 1 Seminals Daily lcStiCules Vesiculs Prostate Surrenals Doses in mg in mg in mg in mg Controls 2 900 761.6 462.6 42.6

Product 2007 2 600 591.1 363.9 36.7

(22%) (-2l7r) 1 mg 2 700 397.9 240.3 39.0

The results of Table 1 show that the product has antigonadotrophic activity with a clear anti LH predominance and does not provoke surrenalien aplasia.

B. Exogenic Antiandrogenic Activity This activity was determined with testosterone propionate on castrated male rats by the Lerner method described by Dorfman in Methods in Hormone Research, 11, p. 320. The 4-week old male rats were castrated and the treatment was started the next day and lasted for 7 days. On the 8th day. the animals were killed and the prostate. seminal vesiculs and levator ani were recovered. The two products were used as solutions in sesame oil containing percent benzyl alcohol and were separately administered subcutaneously. The test product was administered at a dose of 1 mg and testosterone propionate was administered at a dose of 507. A control group received only the solvent, a second group received 507 of testosterone propionate subcutaneously, a third group received subcutaneously 507, 2007 or 1 mg of 7a-methyl-l9-nor-A" "'-pregnatriene-3,20- dione and the fourth group received subcutaneously 507 of testosterone propionate and 507, 2007 or 1 mg of the said test product. The results are reported in Table 11.

TABLE 11 Fresh Daily Levator Seminals (iroup Doses uni in Vesiculs Prostate mg in mg in mg Controls (1 37.1 16.9 19.2 Testosterone 507 48.7 122.5 156.6 Propionate Test Product 507 31.7 12.5 19.3 Test Product 507 'lestosterone 84.2 1 18.7 Propionate 507 49.3 (-217!) (26'/r) Test Product 2007 42.3 7.9 1.5.5 Test Product 200 Testosterone 64.2 82.2 105.2 Propionate 507 (23'/r (33?4) Controls 0 39.1 16.5 17.0 Testosterone 507 MM 101.) t 19.5 Propionate Test Product 1 mg 37.2 30.2 44.) Test Product 1 mg Testosterone 38.4 51.1 60.9 Propiounte 507 (39% (-40%) The results of Table 11 show that the said product of the invention has an important exogenic antiandrogenie activity at a dose of 507 against testosterone propionate.

C. Antiestrogenic Activity The antiestrogenic activity of 7a-methyl-l9-nor- A -pregnatriene-3.20-dione was determined on impuberic mice by a technique inspired byRubin [End0.,

Vol. 49 1951 p. 429] and the related test of Dorfman et al. [Methods in Hormone Research, Vol. 11 (1962),

p. l 18 l. The estrogen used was estradiol and mice aged 19 to 21 days received a daily subcutaneous injection for 3 days of estradiol alone, the test product alone or 5 estradiol and the test product. In the last case, the two steroids were injected at different parts. The mice were killed on the 4 th day and the uterus was removed and weighed. Estradiol was administered in a sesame oil solution containing 5 percent of benzyl alcohol at a total dose of 0.277 with each injection having a volume of 0.1 ml per mouse. The test product was administered in the same solution at a total does of 10, or 907 with each injection having a volume of 0.1 ml per mouse. The results are reported in Table 111.

30 Table 111 shows that the test compound has a clear antiestrogenic activity against 0.277 of estradiol at a dose of 907.

D. Progestomimetic Activity v The progestomimetic activity was determined by the Clauberg test on immature rabbits previously sensitized by subcutaneous administration of a daily dose of 107 of estradiol benzoate over 5 days. The animals were then treated for 5 days with subcutaneous administration of 50 or 2007 of 7a-methyl-19-nor-A "'-pregnatriene-3,20-dione in solution in olive oil containing 5 percent benzyl alcohol. The animals were killed on the 6th day and the uterus was cut and examined for proliferation of endometric lace characteristic of progestomimetic acitivity in MacPhail units. The results are reported in Table 1V.

TABLE [V Product Daily MacPhil Dose Units 7a-methyl-19-nor-A"-"- 507 0.5

pregnatricne-3.20-dione 200 3.5

The results of Table IV show that the said product has an important progestomimetic activity at a daily dose of 2007.

Various modifications of the products and methods of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended cliams.

We claim:

1. A 7a-methyl-13,8-alkyl-18.l9-dinor-A pregnatriene-3.20-dione of the formula R20 cm wherein R and R have the above definition and R, and R are alkyl of one to five carbon atoms or together form an alkylene of two to four carbon atoms to acid hydrolysis to form a compound of the formula reacting the latter with a hydroperoxidation agent to form a compound of the formula 3 R] CCH3 HOO l5 O- CHg reducing the latter with a reducing agent to form a compound of the formula Q l 35 R iicn;

uo Y o:k --cni and dehydrating the latter with a mineral acid to form the corresponding compound of claim I. z 

2. A compound of claim 1 which is 7 Alpha -methyl-19-nor- Delta 4,9,11-pregnatriene-3,20-dione.
 3. A process for the preparation of a compound of claim 1 comprising subjecting a ketal of the formula 